The First Clinical College, Hubei University of Chinese Medicine, Wuhan, China.
College of Clinical Chinese Medicine, Hubei University of Chinese Medicine, Wuhan, China.
Environ Toxicol. 2024 Feb;39(2):751-767. doi: 10.1002/tox.23974. Epub 2023 Sep 26.
An increasing number of studies have shown that oxidative stress plays an important role in the development and progression of cancer. Cervical cancer (CC) is a disease of unique complexity that tends to exhibit high heterogeneity in molecular phenotypes. We aim here to characterize molecular features of cervical cancer by developing a classification system based on oxidative stress-related gene expression profiles. In this study, we obtained gene expression profiling data for cervical cancer from the TCGA (The Cancer Genome Atlas) and GEO (Gene Expression Omnibus) (GSE44001) databases. Oxidative stress-related genes used for clustering were obtained from GeneCards. Patients with cervical cancer were divided into two subtypes (C1 and C2) by non-negative matrix factorization (NMF) classification. By performing Kaplan-Meier survival analysis, differential expression analysis, and gene set enrichment analysis (GSEA) between the two subtypes, we found that subtype C2 had a worse prognosis and was highly enriched for immune-related pathways as well as epithelial-mesenchymal transition (EMT) pathways. Subsequently, we performed metabolic pathway analysis, gene mutation landscape analysis, immune microenvironment analysis, immunotherapy response analysis, and drug sensitivity analysis of the two isoforms. The results showed that the isoforms were significantly different between metabolic pathway enrichment and the immune microenvironment, and the chromosomes of subtype C1 were more unstable. In addition, we found that subtype C2 tends to respond to treatment with anti-CTLA4 agents, a conclusion that coincides with high chromosomal variation in C1, as well as C2 enrichment of immune-related pathways. Then, we screened 10 agents that were significantly susceptible to C2 subtype. Finally, we constructed pathogenomics models based on pathological features and linked them to molecular subtypes. This study establishes a novel CC classification based on gene expression profiles of oxidative stress-related genes and elucidates differences between immune microenvironments between CC subtypes, contributing to subtype-specific immunotherapy and drug therapy.
越来越多的研究表明，氧化应激在癌症的发生和发展中起着重要作用。宫颈癌（CC）是一种具有独特复杂性的疾病，其分子表型往往表现出高度异质性。我们旨在通过开发基于氧化应激相关基因表达谱的分类系统来描述宫颈癌的分子特征。在这项研究中，我们从 TCGA（癌症基因组图谱）和 GEO（基因表达综合数据库）（GSE44001）数据库中获得了宫颈癌的基因表达谱数据。用于聚类的氧化应激相关基因从 GeneCards 中获得。通过非负矩阵分解（NMF）分类，将宫颈癌患者分为两个亚型（C1 和 C2）。通过进行 Kaplan-Meier 生存分析、差异表达分析和两个亚型之间的基因集富集分析（GSEA），我们发现亚型 C2 的预后较差，并且富含免疫相关途径和上皮-间充质转化（EMT）途径。随后，我们对两个亚型进行了代谢途径分析、基因突变景观分析、免疫微环境分析、免疫治疗反应分析和药物敏感性分析。结果表明，在代谢途径富集和免疫微环境中，两个亚型的基因存在显著差异，且 C1 亚型的染色体稳定性较差。此外，我们发现 C2 亚型倾向于对 CTLA4 抑制剂治疗有反应，这一结论与 C1 中染色体的高度变异性以及 C2 中免疫相关途径的富集相一致。然后，我们筛选出了对 C2 亚型有显著敏感性的 10 种药物。最后，我们基于病理特征构建了病原体组学模型，并将其与分子亚型相关联。本研究基于氧化应激相关基因表达谱建立了一种新的宫颈癌分类方法，并阐明了宫颈癌亚型之间免疫微环境的差异，有助于针对特定亚型的免疫治疗和药物治疗。
